A Smiles rearrangement describes a pattern of reactions involving intramolecular nucleophilic aromatic substitution which results in the replacement of one heteroatom to another on an aromatic ring and works with a variety of heteroatoms, including oxygen, sulfur and nitrogen. A Smiles rearrangement of phenols, including fused-ring heterocyclic phenols, into corresponding anilines is described by I. G. C. Coutts and M. R. Southcott in J. Chem. Soc. Perkin Trans. I, 1990;767-771, where the hydroxy group on an aromatic ring, optionally fused into a larger ring system, is replaced with an amino group. However, Coutts and Southcott describe the synthesis as a distinct three-step process, with the purification of each intermediate. The first step is a conversion of the alcohol to a 2-aryloxyacetamide. The second step is the actual Smiles rearrangement of the aryloxyacetamide to a 2-hydroxy-N-arylacetamide. Finally, the 2-hydroxy-N-arylacetamide is hydrolyzed to the corresponding aromatic amine. The known Smiles rearrangements of aromatic amides involves purification of the 2-aryloxyacetamide intermediates.
A simplified Smiles rearrangement which avoided purification of the 2-aryloxyacetamide intermediates was recently described in J. J. Weidner, P. M. Weintraub, and N. P. Peet, 209th National Meeting of the American Chemical Society, Mar. 24-29th, 1996, New Orleans, La., ORGN 54. This process provided a concise route to 3-aminoestratrienes and is exemplified by conversion of estrone to the corresponding amino derivative by a Smiles rearrangement of a 2-aryloxyacetamide to a 2-hydroxy-N-arylacetamide.
The Bucherer reaction is a method of direct conversion of hydroxypyridines and related heterocycles to their amino derivatives. The Bucherer reaction is a well-documented method for direct conversion of hydroxynaphthalenes, hydroxyquinolines, and related heterocycles to their corresponding amines. This reaction is described in Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 3rd edition, John Wiley and Sons, New York, 1985, p. 591-592, incorporated by reference herein. Numerous literature references exemplify the utility of the Bucherer reaction. For example, E. C. Hurdis, J. Org. Chem., 1958, 23; 891-89, describes conversion of 8-hydroxyquinoline to 8-aminoquinoline in high yield by application of this reaction. In a similar manner, a series of substituted 8-aminoquinolines was recently synthesized as starting materials for the preparation of substituted 1,10-phenanthrolines. P. Belser, S. Bernhard and U. Guerig, Tetrahedron, 1996, 52(8); 2937-2944. 8-Aminocinnoline has been obtained from 8-hydroxycinnoline by this methodology. E. J. Alford, H. Irving, H. S. Marsh and K Schofield, J. Chem. Soc., 1952; 3009-3017. A series of derivatives of lysergic acid was synthesized using a similar protocol. A. Stoll, T. Petrzilka Helv. Chim. Acta, 1953, 36; 1125-1137.
Despite the demonstrated utility of the Bucherer method, there are several serious drawbacks. It requires the use of corrosive liquid ammonia in sealed vessels at high temperatures. Along with these potential dangers, the scale is limited without the use of large specialized equipment. Substrates are limited to those resistant to high temperatures and basic conditions. Reactions may also take up to a week to go to completion.
Therefore, there is a need for a general method for converting hydroxypyridines to their corresponding amino derivatives which is applicable to a broad range of hydroxypyridines, does not require the use of liquid ammonia or sealed vessels, is easy to scale up, requires few steps and produces good yields.